title: Digenic mutational inheritance of the integrin alpha 7 and the myosin heavy chain 7B genes causes congenital myopathy with left ventricular non-compact cardiomyopathy.
abstract: BACKGROUND
  We report an Italian family in which the proband showed a severe phenotype characterized by the association of congenital fiber type disproportion (CFTD) with a left ventricular non-compaction cardiomyopathy (LVNC). This study was focused on the identification of the responsible gene/s.
  
  
  RESULTS
  Using the whole-exome sequencing approach, we identified the proband homozygous missense mutations in two genes, the myosin heavy chain 7B (MYH7B) and the integrin alpha 7 (ITGA7). Both genes are expressed in heart and muscle tissues, and both mutations were predicted to be deleterious and were not found in the healthy population.The R890C mutation in the MYH7B gene segregated with the LVNC phenotype in the examined family. It was also found in one unrelated patient affected by LVNC, confirming a causative role in cardiomyopathy.The E882K mutation in the ITGA7 gene, a key component of the basal lamina of muscle fibers, was found only in the proband, suggesting a role in CFTD.
  
  
  CONCLUSIONS
  This study identifies two novel disease genes. Mutation in MYH7B causes a classical LVNC phenotype, whereas mutation in ITGA7 causes CFTD. Both phenotypes represent alterations of skeletal and cardiac muscle maturation and are usually not severe. The severe phenotype of the proband is most likely due to a synergic effect of these two mutations.This study provides new insights into the genetics underlying Mendelian traits and demonstrates a role for digenic inheritance in complex phenotypes.
authors.affiliation: Institute of Genetics and Biophysics, National Research Council of Italy, Naples, Italy. teresa.esposito@igb.cnr.it
authors.forename: Teresa
authors.initials: T
authors.lastname: Esposito
authors.forename: Simone
authors.initials: S
authors.lastname: Sampaolo
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Limongelli
authors.forename: Antonio
authors.initials: A
authors.lastname: Varone
authors.forename: Daniela
authors.initials: D
authors.lastname: Formicola
authors.forename: Daria
authors.initials: D
authors.lastname: Diodato
authors.forename: Olimpia
authors.initials: O
authors.lastname: Farina
authors.forename: Filomena
authors.initials: F
authors.lastname: Napolitano
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pacileo
authors.forename: Fernando
authors.initials: F
authors.lastname: Gianfrancesco
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Di Iorio
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000737:chemistry / Q000235:genetics*; D024722:Cardiac Myosins / Q000737:chemistry / Q000235:genetics*; D009202:Cardiomyopathies / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology*; D002648:Child; D002675:Child, Preschool; D059472:Exome; D005260:Female; D006352:Heart Ventricles / Q000002:abnormalities*; D006801:Humans; D039001:Integrin alpha Chains / Q000737:chemistry / Q000235:genetics*; D007558:Italy; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D018995:Myosin Heavy Chains / Q000737:chemistry / Q000235:genetics*; D009224:Myotonia Congenita / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology*; D010375:Pedigree; D010641:Phenotype; D017422:Sequence Analysis, DNA; D055815:Young Adult
chemical_list: D015703:Antigens, CD; D039001:Integrin alpha Chains; C501641:MYH7 protein, human; C085725:integrin alpha7; D024722:Cardiac Myosins; D018995:Myosin Heavy Chains